Treatment of intestinal dysbiosis, including pathogenic bacteria, candidiasis, and parasites.

What follows includes review and discussion of dietary protocols most commonly utilized in the treatment of ADHD. The medical literature reviewed here includes reports on many of these treatment strategies. Unfortunately, studies on these and other dietary approaches have not shown consistent or reliable effects. Shortcomings in study design and in protocols for selection of therapies appropriate to the individual will be discussed.

Some children and adults with ADHD have responded favorably to a relatively high-protein, low (or complex)- carbohydrate, sugar-free diet. Although the reported benefits are primarily anecdotal, the literature does include some reference to a calming effect and improved learning with such diets. (Conners, 1987; Prinz). There appears to be no reliable predictor of the efficacy in treating ADHD with these changes in diet, although the advocates will often suggest such guidelines for a nutritionally sound dietary foundation. Diets high in sugar and refined carbohydrates tend to be associated with poor nutrient density, inadequate vitamins and minerals, and low dietary fiber, contributing to malnutrition. In at least some vulnerable children, high-sugar diets may also aggravate or potentiate disturbances in blood sugar control, disturbances in bowel flora, and the increased production of inflammatory reactions in metabolism (advanced glycosylation end-products).

Hyperinsulinism with low blood sugar may be a factor in aggressive and irritable behavior seen in ADHD patients (Walker). Screening for dysinsulinism with a glucose/insulin tolerance test may be indicated. This is especially true in cases where there is a family history of glucose intolerance and/or diabetes, as hyperinsulinemia with or without hypoglycemia may indicate a prediabetic condition.

The majority of studies designed to look at sugar consumption in ADHD children have failed to show a significant or causal relationship (review articles: Krummel; Wolraich; Kanarek) Generally, it has been shown that children with ADHD tend to eat no more sugar than average (Kaplan). Simply giving sugar or sweets has also failed to aggravate hyperkinesis compared to control, aspartame-sweetened foods. (Roshon)

In spite of the apparent rejection of diet therapy in the literature, a diet low in sugar and other foods with "empty calories" remains a featured component of the treatment for many children with ADHD, reflecting beliefs of parents and teachers (Bussing; Barbaresi). The inconsistent and negative reports from the literature may be due, in part, to poor study design, and trials have been met with criticism. Methodological shortcomings include:

Only sugar (sucrose) was assessed, not using or accounting for the significant intake of other dietary sugars which include corn syrup, high fructose corn syrup, glucose, fructose, etc.

Only acute, shortterm effects were studied.

Reactions to sugar in many children may result from particular food interactions, including other food components, additives, and caramelization of carbohydrate starches in toasted grains and cereals, etc. A high carbohydrate diet (ie breakfast cereal with sugar) may have a greater effect on behavior than dietary sugar alone.
(Conners, 1985)

Increasing carbohydrate/protein ratio may cause drowsiness and behavioral reactions as well as a decline in cognitive function due to errors in glucose metabolism.

In one study it was shown that protein metabolism in some hyperactive boys differs significantly from normal.(Stein) The researchers used a tracer (15N glycine) to measure excretion, flux, and whole-body protein synthesis. It was also noted that height and weight correlated inversely with ADHD, and that the hyperactive children experienced greater nitrogen excretion. Implications of this study are that there may be an increase demand for dietary protein in certain hyperactive children.

A detailed review of the controlled scientific literature regarding the role of diet and behavior in childhood (Breakey,) has shown that diet definitely effects some children. The issue has become more complex however as the range and magnitude of food reactions come into the equation.(Schauss) Although it appears from several studies that sugar consumption is not the primary causative factor in ADHD, there are some children for whom hypoglycemia and/or dysinsulinemia play a critical role. A glucose-insulin tolerance test may help differentiate these children. Beyond the issue of sugar reactivity, the health consequences of a diet high in the "empty calories" may contribute to the malnutrition and nutrient deficiencies commonly seen in these children. Diets to correct these deficiencies and imbalances may take time and consistency before the full benefits become evident. Studies that simply evaluate a short-term trial of dietary sugar loading or avoidance may fail to detect the benefits that occur from lasting dietary changes.

RELATED STUDIES:

Glucose Tolerance and Hyperkinesis

Langseth & Dowd
Food Cosmet. Toxicol. 16:129-33, 1978

261 hyperactive children were given 5-hour GTTs . 74% of these had abnormally flat glucose response curves.

Blunted Catecholamine Responses After Glucose Ingestion in Children with Attention Deficit Disorder

Girardi NL, et al.
Pediatr Res 1995 Oct;38(4):539-42

Eating simple sugars has been suggested as having adverse behavioral and cognitive effects in children with ADD, but a physiologic mechanism has not been established. To address this issue, metabolic, hormonal, and cognitive responses to a standard oral glucose load were compared in 17 children with ADD and 11 control children.

Although baseline and oral glucose-stimulated plasma glucose were similar in both groups, the ADD group showed a diminished epinephrine (50% lower) response compared to control children. (Normally, as the glucose goes down at 3-5 hours after the glucose load, there is a notable rise in epinephrine, raising blood sugar to baseline. This normal rise was diminished in the ADD group.) Matching test scores were lower and reaction times faster in ADD compared to control children. These data suggest that children with ADD have a general impairment of sympathetic activation.

The prevalence of food sensitivities in ADHD patients is generally acknowledged, although the clinical significance and management of these often-subtle reactions remains subject to much debate. At issue in the controversy is the interpretation of the terms "allergy" and "sensitivity". The importance of acute food allergies, IgE-mediated, are well known and generally accepted as clinically relevant. However, the identification of sub-acute food reactions, food intolerance and sensitivities, are subject to debate as to their clinical meaning. Such food sensitivities are generally thought to be IgG-mediated reactions, sometimes called delayed hypersensitivies. Again, studies to delineate delayed hypersensitivies to food are often criticized for having methodological flaws.

Several double-blinded dietary trials have been able to demonstrate that food sensitivities may sometimes provoke hyperkinesis and other ADHD behavior changes, and that elimination of the identified foods has caused an improvement in behavior. (Boris; Schmidt; Carter; Egger 1985) A hypoallergenic (oligoantigenic) diet has also been shown to prevent bedwetting and migraines in some hyperactive children. (Egger 1992).

Elimination of Allergens:

The elimination of allergens helps some children with ADHD.

RELATED STUDIES:

Effects of a Few Food Diet in Attention Deficit Disorder

Carter CM, et al.
Arch Dis Child 1993 Nov;69(5) :564-8

74 children referred for treatment of ADHD were placed on a few foods elimination diet. 59 improved in behavior during this open trial. For 19 of these children it was possible to disguise foods or additives, or both, that reliably provoked behavioral problems, to test their effect in a placebo-controlled double blind challenge protocol. The results of a crossover trial of these 19 children showed a significant effect for the provoking foods to worsen rating of behavior and to impair psychological test performance. This demonstrated that observations about dietary effects on behavior can be reproduced using double blind methodology and objective measurements. Clinicians should give weight to the accounts of parents and consider this treatment in children with a suggestive medical history.

A cross-over placebo-controlled, double-blind design was used to examine the effectiveness of an oligoanitgenic diet in 49 children with hyperactive/disruptive behavior disorder. Effects were compared to stimulant medication (methylphenidate,= Ritalin). 12 children (24%) showed significant behavioral improvement in two behavior ratings during (oligoantigenic) diet compared to control diet conditions. The improvements in those taking medication yielded more responders (44%) than diet alone.

Although diet changes alone will not be helpful in every case, it is clear that special diets are effective in many children with attention deficit. A good patient history with other indications of allergy will help in the selection of those appropriate for elimination diets. There are several strategies for assessing food sensitivities that have been utilized in complementary medical practices:

Therapies are generally focused on removal of common or identified allergens and food sensitivities from the diet, and substitution with foods of low antigenic potential.

Some common allergenic foods:

wheat (or refined flour)

peanuts

milk

cheese

sugar

corn syrup

barley

eggs

corn

rye

chocolate

soy

oats

The selective introduction of special oligoantigenic food supplements (with low allergenic potential), and devised meal plans often help to accomplish this. A rice beverage may substitute for cow milk. Hydrolyzed whey protein, for example, is often tolerated in dairy-allergic patients and may be added to rice beverage for additional protein and immune enhancement. Some wheat-allergic children tolerate other grains such as spelt, millet, and rice. Wheat-free breads are available at most health-food stores. Sensitive children may tolerate sweetening with rice-syrup solids better than sugar or corn syrup. Lab testing, trial elimination diet, or some alternative form of screening for food sensitivities may help make the choice of appropriate foods more feasible and accurate.

Alternative and complementary approaches to dealing with food sensitivities include:

Treatments for "intestinal permeability" or "leaky gut syndrome":

This is based on the finding that reactive and inflammatory bowel states sometimes cause damage to the brush-border lining of the intestine, leading to a high concentration of dietary protein and food antigens crossing over into the blood stream and consequently triggering multiple allergies. The therapy consists of special supplements containing probiotic factors such as amino acids, glutamine, hydrolyzed whey protein (globulins, lactoferrin), gamma oryzonol from rice oil, and other essential nutrients and EFAs. As the gut lining repairs itself the propensity toward allergy is diminished. (see notes on testing: intestinal permeability)

Practiced by some acupuncturists, NDs, and DCs, this technique involves energetic (mind-body) clearing of reactivity to foods. Proponents of this technique offer the explanation that the immune and nervous system components of food reactions are altered and the body no longer reacts as if the food items are "foreign" to their system.

In the 1970s Benjamin Feingold, MD, popularized the concept that ADHD is caused and aggravated by intolerance to food additives and salicylates. The "Feingold hypothesis" made a case for the negative effects of food additives and preservatives, especially the artificial colors so predominant in diets of children with ADHD. Dr. Feingolds experience suggests that up to 50% of hyperactive children are sensitive to these chemicals. His claims were based on over 1,200 cases in which food additives were linked to behavior and learning disorders. His program also implicated a reaction to salicylates, not only from asparin, but salicylates naturally occurring in foods as well. He presented his findings to the AMA in 1973. (Feingold)

200 ADHD children were included in this 6-week open trial of a diet free of synthetic food coloring. Parents of 150 children reported improvement on the diet, with deterioration on the reintroduction of restricted items. A behavioral inventory, based on parents observations, was devised to classify the children as "suspected reactors".

20 hyperactive children were given varying amounts of food dyes 26 mgs, 75 mgs, 100mgs, and 150 mgs. It was found that at 26 mgs there was no change in the childrens behavior, but at the higher doses 17 of the 20 children had significant impairment of learning performance.

Many researchers who have set out to test the Feingold hypothesis have either failed to confirm the findings, or have produced inconclusive results. (Mattes; Adams; Stare; Harner; Harley). The National Advisory Committee on Hyperkinesis and Food Additives to the USA Nutrition Foundation in 1980 filed a negative report about the role of food additives and hyperactivity.

Much of the research used to test the effects of artificial food colors and other additives has shown an insignificant relationship between these chemicals and hyperactive behavior. In spite of this, the notion that sugar and chemicals in the diet may aggravate ADHD symptoms remains a widely held presumption amongst parents, teachers, and most alternative medical practitioners. Several criticisms have been raised regarding the validity of studies on both sides of this debate. Criticism has been placed in several areas:

Groups receiving the food additives have (in some cases) received far less in amount and/or variety compared to the average amounts normally consumed by these and other children.

Studies have indicated that certain nutritional supplements may be beneficial in ADHD. It has been argued that ADHD is not simply a disease of malnutrition however, as studies have shown that the diets of normal children do not differ significantly from those with the disorder. The concept of "biological individuality" suggests that these children may have unusual, genetically determined biological requirements. The underlying metabolic stress and indicated nutritional support may likely vary from one child to another.

This equation may depend not only on diet, digestion and assimilation of nutrients, but also on the individuals genetic potential, exposure to environmental stresses, allergies, their concurrent use of medications, and so forth. The success or failure of a specific nutritional trial may be misunderstood in terms of its ability to predict results in a case by case approach. It becomes clear to those practicing nutrition-based medicine that a multifactorial disorder such as ADHD requires a broad understanding of nutritional principles, diagnostic screening, environmental interactions, and therapeutic programs tailored to the individual.

As with other nutrition-related studies of ADHD, criticism of the mega vitamin-mineral literature has centered around issues of study design, including the issues of relative individual absorption rates, compliance, observation of behavior, and duration of study. The understanding that emerges from failure of single-therapy trials may be a factor of failure in pre-treatment screening and selection of appropriate subjects for the particular metabolic treatment in question. Lab and other methods of screening could allow for the assignment of appropriate interventions.

Many nutrient deficiencies are implicated in behavior disorders. According to human physiology and nutrition theories, cellular function, and particularly brain function, is partially dependent upon nutritional status.(Essman). The stages of nutrient deficiency, from low intake through low blood nutrient concentrations to eventual compromised function are well documented for selected nutrients. For example, pyridoxine deficiency may cause impairment of neuronal activity, neurotransmitter imbalances, poor conversion of tryptophan to serotonin, and eventually may manifest as EEG abnormalities.(Sizer)

Testing for nutritional status in ADHD has typically involved laboratory assays for nutrients, including the following examples:

serum vitamins, or functional tests of vitamin reserve

minerals (most commonly hair and/or RBC minerals),

serum iron or ferritin,

essential fatty acids (EFAs) in plasma and RBCs,

serum or urinary amino acids

urinary organic acids.

Links to further information regarding these tests are referenced later in this article.

A review of the literature on ADHD provides modest evidence for generalized treatment with vitamins. The beneficial effects of vitamin therapies appear to be limited to particular subsets of ADHD subjects with particular nutrient deficiencies known to impair function, and in individuals with biological demands for increased levels of nutrients. This is a concept familiar to those practicing biological or functional medicine.

Evidence for nutrient-mediated defects and effects of specific nutrient therapies in ADHD follow:

A Preliminary Study of the Effect of Pyridoxine Administration in a Subgroup of Hyperkinetic Children: a Double-blind Crossover Comparison with Methylphenidate

Coleman M, et al
Biol Psychiatry 1979 Oct; 14(5):741-51

6 children with low whole blood serotonin were given pyridoxine, methylphenidate, or placebo. Both pyridoxine and methylphenidate were more effective than placebo in suppressing symptoms of hyperkinesis. Pyridoxine increased levels of serotonin, methylphenidate did not. Both clinical and laboratory evidence indicated that the pyridoxine effects persisted beyond the three-week period when the vitamin had been given. Again, this study points to the need of select individuals for larger doses of vitamins to restore normal function.

A Pyridoxine-dependent Behavioral Disorder Unmasked by Isoniazid.

Brenner A, Wapnir RA
Am J Dis Child 1978 Aug;132(8):773-6

A 3-year-old girl had behavioral deterioration, with hyperkinesis, irritability, and sleeping difficulties after the therapeutic administration of isoniazid. The administration of pharmacologic doses of pyridoxine hydrochloride led to a
disappearance of symptoms. After discontinuing isoniazid therapy a similar pattern of behavior was noted that was controlled by pyridoxine. A placebo had no effect, but niacinamide was as effective as pyridoxine. Periodic withdrawal of pyridoxine was associated with return of the hyperkinesis. The level of pyridoxal in the blood was normal during the periods of relapse. Metabolic studies suggested a block in the kynurenine pathway of tryptophan metabolism. The patient has been followed for six years and has required pharmacologic doses of pyridoxine to control her behavior.

Of note in the above study is that in this case there was no deficiency of B-6 by normal standards. The treatment did not require a documentation of deficiency, rather a pharmacological (large-dose) use of the vitamin to overcome metabolic, genetic defects. This represents another case in point for biological individuality and the need in some for vitamins, sometimes in mega-doses.

Niacinamide Used in Children with Severely-disturbed or Psychotic Behavior:

RELATED STUDIES:

Vitamin B3-dependant Child

Hoffer A
Schizophrenia 3:107-113, 1971

In this study 33 children under the age of 13 with disturbed behavior were placed on nicotinamide (B-3) with doses from 1.5 to 6 gms daily along with 3 gms of ascorbic acid.

Only 1 out of 33 failed to respond to the B-3 therapy. All of the responders then relapsed upon substitution with placebo, and then improved again upon restarting the B-3.

Note that this study was not designed to evaluate a treatment for the typical ADHD patient, but rather a special subgroup of extremely-disturbed children. Hoffer has also championed B-3 protocols in the biological treatment of schizophrenia, and offers a biochemical model for metabolic effects to address unique needs of this group. Megadose niacinamide failed to demonstrate an effect on groups of ADHD children in other clinical trials. (Haslam; Kershner)

The Effects of Megadoses of Selected B-complex Vitamins on Children with Hyperkinesis: Controlled Studies with Long-term Follow-up

Brenner A
J Learn Disabil 15(5):258-64, 1982

This study followed a group of 100 children, aged 4  25 years, with hyperkinesis and minimal cerebral dysfunction syndrome. The children were given daily supplements of 100 mg thiamine, to be given 4 times per day. Following a short trial, children received either thiamine or placebo in a double blind crossover designed trial. About 25% of the children responded dramatically to the thiamin supplement, and about half of these relapsed while taking the placebo. A significant number of children in this study also responded to pyridoxine (B-6) supplements.

Studies have shown that, at least in some malnourished children, vitamin supplementation will increase non-verbal IQ. (Benton; Nelson; Crombie). It has been hypothesized that the significant gains in IQ (+2.5 points average) seen in large clinical trials was actually due to relatively large gains (+15 points) in a select few (15%) of the children. It was presumed that these responsive children represented the subgroup of those with less than adequate nutritional status going into the study.

NEGATIVE RELATED STUDIES:

Effects of Megavitamin Therapy on Children with Attention Deficit Disorders

Haslam RH, Dalby JT, Rademaker AW
Pediatrics 1984 July;74(1):103-11

In this trial of megavitamin therapy, 41 children with ADHD where given high doses of vitamins (daily maximum: 3 g niacinamide, and ascorbic acid, 1.2 g of calcium pantothenate, and 0.6 g of pyridoxine) for three months. After this the children received either vitamins or placebo in 6-week intervals. Although 29% of them showed significant behavior improvement during the first 3-month vitamin phase, this benefit did not hold up to the double blind crossover phase of the study. There was no significant difference between children receiving vitamins and those receiving placebo during phase two. It was concluded that megavitamins are ineffective in the management of ADHD.

Again, studies designed to address the subset of ADHD with vitamin deficiencies, or increase demands for these nutrients, will more likely to respond the indicated megadose vitamin therapy. Such selection will likely require careful screening the larger population of ADHD patients for metabolic errors and other indications for the protocol.

Studies of hair and blood have demonstrated mineral deficiencies in ADHD. The most consistent findings are low magnesium (Kozielec 1994; Kozielec 1997; Starobrat-Hermelin) and low zinc (Barlow; Bekaroglu M; Kozielec 1994). Iron deficiencies have also been linked to certain cases of ADHD (Kozielec 1994; Sever; Tu; Burattini). Studies of mineral status have also revealed a patterns of toxic mineral burden, most notably manganese (Barlow 1983; Collipp), lead ( Needleman;Tuthill;Eppright ), cadmium (Ward; Stewrt-Pinkham) and aluminum (Barlow 1986; Howard; Ward ). Implications and management of heavy metal toxicity will be addressed in a later section of this article.

RELATED STUDIES:

The Effect of Deficiency of Selected Bioelements on Hyperactivity in Children with Certain Specified Mental Disorders

Starobrat-Hermelin B
Ann Acad Med Stetin 1998;44:297-314

In this study of 116 ADHD children, the investigator found significant deficiencies of magnesium, copper, zinc, calcium, and iron (in blood and hair). Of 75 children with documented magnesium deficiency, 50 were placed on a magnesium supplement for 6 months, while the remaining 25 continued with conventional therapy, without additional magnesium. At the end of this study all 75 children were again evaluated for mineral levels.

The post-test findings revealed higher levels of magnesium, zinc, and calcium and respectively essential decrease in hyperactivity in the group of children treated with magnesium. At the same time, however, among the children given standard treatment without magnesium, hyperactivity has intensified.

The study concludes that there is a need for magnesium supplementation in ADHD, and that taken together with conventional modes of treatment provides opportunities to extend benefits to "children of the risk" who might otherwise fail to respond.

Assessment of Magnesium Levels in Children with Attention Deficit Hyperactivity Disorder (ADHD)

Kozielec T, Starobrat-Hermelin B
Magnes Res 1997 Jun;10(2):143-8

The aim of this work was to estimate magnesium contents in children with attention deficit hyperactivity disorder, (ADHD). The investigations comprised 116 children (94 boys and 20 girls), aged 9-12 years, with recognized ADHD. Magnesium levels have been determined in blood serum, red blood cells and in hair with the aid of atomic absorption spectroscopy. Magnesium deficiency was found in 95 per cent of those examined, most frequently in hair (77.6 per cent), in red blood cells (58.6 per cent) and in blood serum (33.6 per cent) of children with ADHD.

The conclusion from the investigations is that magnesium deficiency in children with ADHD occurs more frequently than in healthy children. Analysis of the material indicated a correlation between increasing levels of magnesium and freedom from distractibility.

The Effects of Magnesium Physiological Supplementation on Hyperactivity in
Children with Attention Deficit Hyperactivity Disorder (ADHD): Positive Response
to Magnesium Oral Loading Test

Starobrat-Hermelin B, Kozielec T
Magnes Res 1997 Jun;10(2):149-56

It is reported that dietetic factors can play a significant role in the etiology of ADHD syndrome, and magnesium deficiency can help in revealing hyperactivity in children. The aim of this work was to assess the influence of magnesium supplementation on hyperactivity in patients with ADHD. The examination comprised 50 hyperactive children, aged 7-12 years, who fulfilled DSM-IV criteria for ADHD syndrome, with recognized deficiency of magnesium in the blood (blood serum and red blood cells) and in hair using atomic absorption spectroscopy.

In the period of 6 months those examined regularly took magnesium preparations in a dose of about 200 mg/day. 30 of those examined with ADHD showed coexisting disorders specific to developmental age, and 20 of them showed disruptive behaviour. The control group consisted of 25 children with ADHD and magnesium deficiency, who were treated in a standard way, without magnesium preparations. 15 members of this group showed coexisting disorders specific for developmental age, and 10 members showed disruptive behaviour. Hyperactivity was assessed with the aid of psychometric scales: the Conners Rating Scale for Parents and Teachers, Wender's Scale of Behavior and the Quotient of Development to Freedom from Distractibility.

In the group of children given 6 months of magnesium supplementation, independently of other mental disorders coexisting with hyperactivity, an increase in magnesium contents in hair and a significant decrease of hyperactivity of those examined has been achieved, compared to their clinical state before supplementation and compared to the control group which had not been treated with magnesium.

In 18 boys with ADHD (ages 6-12) in a balanced crossover design, parent and teacher hyperactivity rating differences between one month of dextroamphetamine and one month of placebo correlated significantly (p less than .05, 2 tailed) on Pearson's rating with baseline hair zinc levels and nonsignificantly with 24-hour urinary zinc excretion.

The signs of the correlations were such that a higher baseline zinc predicted a better placebo-controlled response to amphetamine. Patient baseline urinary zinc was significantly (p less than .02) lower than 7 normal controls.

These findings are compatible with the possibility that some ADHD children may be mildly deficient in zinc and constitute poorer stimulant responders. Correlations of zinc levels with 24-hour urinary MHPG were in the expected direction, but nonsignificantly by 2-tailed test.

Note, once again, that evaluation for patterns of individual nutritional need may be critical to produce therapeutic effects and will help determine the appropriate supplemental nutritional regime. Failure to tailor appropriate nutrient therapy to address these underlying functional needs may account for many of the treatment failures seen with single-nutrient trials, or trials of diet or medication therapy alone.

Iron plays a role in the regulation of dopaminergic activity. In the present study, nonanemic children with attention deficit hyperactivity disorder (ADHD) were evaluated with regard to heme and nonheme iron metabolism and the effect of short-term iron administration on behavior. The study group consisted of 14 boys aged 7-11 years. All first underwent testing to rule out other psychiatric and medical problems.

The severity of the ADHD symptoms was determined by parent and teacher scores on the Connors Rating Scale. Thereafter, each patient received an iron preparation (Ferrocal), 5 mg/kg/day for 30 days. Blood samples were taken before and after drug administration. Results showed a significant increase in serum ferritin levels (from 25.9 +/- 9.2 to 44.6 +/- 18 ng/ml) and a significant decrease on the parents' Connors Rating Scale scores (from 17.6 +/- 4.5 to 12.7 +/- 5.4). There were no changes in other blood parameters or in the teachers' scores on the rating scale.

The frequent occurrence of restless legs syndrome in children with ADHD may be associated with iron deficiencies. Some studies have shown a relationship between low iron status and this syndrome that causes restlessness and disturbed sleep in effected individuals.

Hypothesis : A Lack of Essential Fatty Acids as a Possible Cause of Hyperactivity in Children

Colquhoun I, Bunday S
Med Hypotheses 1981 May;7(5):673-9

Many ADHD children have a deficiency of essential fatty acids (EFAs) either because they cannot metabolise linoleic acid normally, or because they cannot absorb EFAs normally from the gut, or because their EFA requirements are higher than normal.

The main pieces of evidence are:

Most of the food constituents which cause trouble in ADHD children are weak inhibitors of the conversion of EFAs to prostaglandins (PGs).

Boys are much more commonly effected than girls and males are known to have much higher requirements for EFAs than females.

A high proportion of ADHD children have abnormal thirst and thirst is one of the cardinal signs of EFA deficiency.

Many of ADHD children have eczema, allergies and asthma which some reports suggest can be alleviated by EFAs.

Many of ADHD children are deficient in zinc which is required for conversion of EFAs to PGs.

Some ADHD children are badly affected by wheat and milk which are known to give rise to exorphins in the gut which can block conversion of EFAs to PGE1.

A preliminary study of EFA supplementation in a number of ADHD children had given promising results.

Long-chain Polyunsaturated Fatty Acids in Children with Attention-Deficit Hyperactivity Disorder

Several previous studies indicated that some physical symptoms reported in ADHD are similar to symptoms observed in essential fatty acid (EFA) deficiency in animals and humans deprived of EFAs. We reported previously that a subgroup of ADHD subjects reporting many symptoms indicative of EFA deficiency (L-ADHD) had significantly lower proportions of plasma arachidonic acid and docosahexaenoic acid than did ADHD subjects with few such symptoms or control subjects. In another study using contrast analysis of the plasma polar lipid data, subjects with lower compositions of total n-3 fatty acids had significantly more behavioral problems, temper tantrums, and learning, health, and sleep problems than did those with high proportions of n-3 fatty acids. The reasons for the lower proportions of long-chain polyunsaturated fatty acids (LCPUFAs) in these children are not clear; however, factors may involve inadequate fatty acid intake, poor conversion of EFAs to LCPUFA products, and enhanced metabolism.

This study hypothesized that some children with ADHD have altered fatty acid metabolism. The present study found that 53 subjects with ADHD had significantly lower concentrations of key fatty acids in the plasma polar lipids (20:4n-6, 20:5n-3, and 22:6n-3) and in red blood cell total lipids (20:4n-6 and 22:4n-6) than did the 43 control subjects. Also, a subgroup of 21 subjects with ADHD exhibiting many symptoms of essential fatty acid (EFA) deficiency had significantly lower plasma concentrations of 20:4n-6 and 22:6n-3 than did 32 subjects with ADHD with few EFA-deficiency symptoms. The data are discussed with respect to cause, but the precise reason for lower fatty acid concentrations in some children withADHD is not clear.

Zinc is required for conversion of EFAs to prostaglandins. It may be helpful to supplement zinc along with essential fatty acids. In one study addressing this consideration, ADHD children were found to be significantly low in both zinc and serum free fatty acids (Bekaroglu) compared to control children.

Healthy Fat:

Supplements of essential fatty acids appropriate for children include those with omega 3 (fish oil, flax oil) and gamma linolenic acid (GLA). Quality omega 3 oils are found in fish oil, such as salmon oil. Flax oil is a common vegetarian source of these oils. Commercially available oil blends sometimes include evening primrose or borage oil to balance other essential fatty acids into the diet.

Diets high in polyunsaturated oils, trans-fatty acids, hydrogenated oils, and other synthetic fats should be restricted. Healthy oils participate in formation of desired forms of prostaglandins that are essential to well-being. Synthetic fats are more likely to have negative metabolic consequences on neuronal membrane function, and prostaglandins, as well as brain function.

A new Omega-3 supplement has been developed by European Reference Botanical Laboratories, Inc. (ERBL). The new product called Coromega comes in an easy-to-use foil packet which doesn't spoil and contains a daily dose of Omega-3.

While the best source of Omega-3 remains cod liver oil and fish oil, this supplement is readily absorbed in the bloodstream. Omega-3 supplements in the past have been known to taste bad. ERBL claims to have solved this problems and says the new product tastes like "orange creamsicles".

Assays of amino acid metabolism have generally revealed imbalances of these essential nutrients in ADHD. Serum amino acid levels as well as other nutrient cofactors may influence synthesis pathways for certain inhibitory and excitatory neurotransmitters. Although the causes for these imbalances remain unknown, the correction of metabolic imbalances through nutritional supplements may be an important component of the overall treatment strategy. Results of clinical trials have been mixed or disappointing for the most part. Some shortcomings of these studies will be discussed.

This study examines plasma amino acids in a group of 28 patients meeting DSM-III criteria for attention deficit disorder (ADD) and 20 control subjects. Compared with controls, the ADD subjects had significantly lower levels of phenylalanine, tyrosine, tryptophan, histidine, and isoleucine. These data suggest a general deficit in amino acid transport, absorption, or both.

Amino Acids and their Metabolites in Blood and Urine of Children with Minimal Cerebral Dysfunction

The following changes were found in children in the minimal cerebral dysfunction: the hypoaminoacidemia and hypoaminoaciduria with decrease of glutamate and aspartate, their amides, methionine and serine in the blood and urine; decrease of lysine, taurine, tyrosine, catecholamines and serotonin in the blood; increase of GABA and glycine in the blood; increase of xanthurenate, proline and cysteine in the urine.

Research in the area of amino acids and ADHD point to a defect in metabolism of and synthesis of neurotransmitters. Simply loading the amino acid precursors to neurotransmitters appears to be of limited clinical benefit, perhaps owing to the failure of such therapies to address the underlying errors of metabolism involved.

Tryptophan is an amino acid precursor to the neurotransmitter, serotonin. Serotonin has neurological functions critical to the ability to relax, sleep, be satisfied or satiated, and is critical to modulation of moods. It has been shown that ADHD children tend to have low serotonin levels, probably due to a disruption in tryptophan-serotonin metabolism. (Comings; Irwin; Hoshino). There appears to be a defect in many of these children effecting this bioconversion.

RELATED STUDIES:

Plasma Free Tryptophan Concentration in Children with Attention Deficit Disorder

In order to examine the serotonin metabolism in children with Attention Deficit Disorder (ADD), plasma tryptophan, which is the precursor of serotonin, wasmeasured in 10 children with ADD and 12 normal children. The mean plasma total tryptophan level in the children with ADD was not significantly different from that of the normal children. The mean plasma free tryptophan level in the children with ADD was significantly higher than that in the normal children. There tended to be a positive correlation between the plasma free tryptophan level and the Werry-Weiss-Peters Activity Scale in children with ADD. In other words, the more severe the hyperactivity of ADD, the higher the plasma free tryptophan level.

The mean ratio of plasma free to total tryptophan levels in the children with ADD was significantly higher than that in the normal children, which means that the children with ADD showed a high amount of free tryptophan in the total tryptophan level. These results suggest that there might be some disturbance in the tryptophan-serotonin metabolism in the brain of a child with ADD.

An open trial of tryptophan supplementation for one week resulted in only minimal improvement (Nemzer) As discussed earlier, vitamin B6 is a cofactor for the synthesis of serotonin from tryptophan, and levels of this vitamin are frequently low in ADHD. Vitamin B6 may help in the bioconversion of tryptophan to serotonin in some ADHD patients with low serotonin. (Coleman; Bhagavan)

Other authors have failed to confirm a deficiency of serotonin in ADHD. (Ferguson). The treatment of ADHD with tryptophan appears to be ineffective for most of ADHD children. Further research is needed to evaluate therapies for serotonin-deficient ADHD children using a combination of tryptophan plus pyridoxine. Also, the use of 5-hydroxytryptohan, a more reliable serotonin precursor, has not been investigated in the subset of ADHD children with low serotonin.

A single-blind study was conducted to evaluate the effect of oral tyrosine on Attention Deficit Disorder (ADD) with hyperactivity in seven outpatient children. Since most biological evidence of ADD supports a norepinephrine or dopamine deficiency, the authors hypothesized that tyrosine, which has been shown to increase catecholamine synthesis, would be beneficial in the treatment of ADD. None of the subjects, however, showed any significant improvement with tyrosine. Implications for the catecholamine deficiency hypothesis and treatment strategies for ADD are discussed.

Eleven hyperactive boys were treated for 2 weeks with D-phenylalanine (20 mg/kg per day) and for 2 weeks with placebo in a double-blind crossover study. Tests included parent and teacher behavior ratings, cognitive measures, and blood and urine measures of norepinephrine, amino acids, and trace amines. No significant improvement or deterioration in behavior and no side effects were noted, and only serum phenylalanine was increased by the active treatment phase. This argues against precursor loading treatment of hyperactivity.

Implications of clinical failures in the therapeutic use of amino acids include ideas for further research. To produce desired effects, for example:

The particular amino acid therapy must be tailored to the biological needs of the population studied, (ie. the subset of ADHD with unique disturbances in amino acid metabolism or the downstream neurotransmitters).

Heavy metal toxicity has been reported in ADHD. Although heavy-metal exposure is an environmental risk that effects ADHD and others alike, significantly greater retention of aluminum (Ward; Howard ) and cadmium (Barlow; Ward) in particular have been observed in ADHD over controls. Lead exposure is also associated with hyperactivity.

Cadmium Toxicity in ADHD:

High cadmium has been detected in some mineral studies of ADHD children. (Ward) Low hair zinc may be a marker for elevations in cadmium.

RELATED STUDIES:

A Pilot Study on the Metal Levels in the Hair of Hyperactive Children

Barlow PJ
Med Hypotheses 1983 Jul;11(3):309-18

The concentration of a number of metals has been determined in the hair of sixty eight children who have been described as 'hyperactive'. These are compared with a control group. The most important findings would appear to be a raised level of manganese and a reduced level of zinc in the hyperactive children. A high manganese level in learning disabled children has also recently been reported and may be of direct relevance this study.

The Effect of Ambient Cadmium Air Pollution on the Hair Mineral Content of Children

Stewart-Pinkham, SM
Sci Total Environ 1989 Jan;78:289-96

Hair analyses of 80 children with learning and behavioral problems were assessed by age, sex, season, place of residence, exposure to passive smoke and excess contact with known cadmium air pollutant sources. All children had been exposed for at least 2 years to air pollution from a refuse-derived fuel incineration plant.

All of the patients had increased hair cadmium compared with a control group, but there was a strong seasonal influence on hair cadmium. Exposure to cadmium was ubiquitous. A neurobehavioral toxic effect was found in children who showed evidence of inhibition of pyrimidine-5'-nucleotidase by low hair phosphorus levels and low zinc levels in whom there was enhanced lead absorption.

Hair analyses appear to be a useful biological monitor for detecting toxic effects from ambient air cadmium levels in subsets of the population at risk for heavy metal toxicity. Air filter measurements appear worthless for detecting environmental contamination with cadmium in air with low levels of lead. Trees, on the other hand, which are more adversely affected by cadmium than other heavy metals, show evidence of inhibition of pyrimidine-5'-nucleosidase by excess seeding.

Lead toxicity and ADHD:

Lead exposure is associated with hyperactivity. There is also a relationship between lead exposure and antisocial behavior. (Needleman, review article.) Although incidences of overt lead poisoning may be relatively rare, the effect of low-level lead exposure may be difficult to fully appreciate. There also appears to be a direct relationship between the levels of lead and the degree of psycho-social and learning impairment in children (Gittelman; Otto; Thomson).

The effect of blood-lead on children's behaviour was investigated in a sub-sample of 501 boys and girls aged 6-9 years from 18 primary schools. Behaviour ratings of the children were made by teachers and parents using the Rutter behaviour scales. An extensive home interview with a parent was also carried out. Multiple regression analyses showed a significant relationship between log blood-lead and teachers' ratings on the total Rutter score and the aggressive/anti-social and hyperactive sub-scores, but not the neurotic sub-score when 30 possible confounding variables were taken into account. There was a dose-response relationship between blood-lead and behaviour ratings, with no evidence of a threshold.

A pilot study was carried out to investigate the relationship between exposure to lead and attention in children. The participants were 43 boys, 8 to 12 years of age, attending special schools for children with educational and/or learning problems (so called LOM schools). Children with probable causes of attentional or memory problems other than lead contamination were excluded from the study.

Various aspects of attention were measured using neuropsychological tests. As an assessment of body lead burden, lead concentration in the boys' hair was measured. Information was collected about variables that possibly could influence attention and/or body lead burden (confounding factors). A multiple regression analysis was used to determine the contribution of lead to variance in performance, after correction for confounding factors.

The results showed that children with relatively high concentrations of lead in their hair reacted significantly slower in a simple reaction-time task than did children with relatively low concentrations of lead in their hair. In addition, the former were significantly less flexible in changing their focus of attention, even after correction for the influence of their delayed reaction time.

The goal of this study was to evaluate the relationship between hair lead levels of children and their attention-deficit behaviors in the classroom. Scalp hair specimens were obtained from 277 first-grade pupils, teachers completed the abbreviated Boston Teacher's Rating Scale for rating classroom attention-deficit behavior, and parents completed a short questionnaire. The children's hair lead concentrations ranged from less than 1 to 11.3 ppm (microg/g).

The striking dose-response relationship between levels of lead and negative teacher ratings remained significant after controlling for age, ethnicity, gender, and socioeconomic status. An even stronger relationship existed between physician-diagnosed attention-deficit hyperactivity disorder and hair lead in the same children. There was no apparent 'safe' threshold for lead. Scalp hair should be considered a useful clinical and epidemiologic approach for the measurement of chronic low-level lead exposure in children.

It appears from these and other studies that body lead burden is associated with impaired neurological function in children. Following this line of reasoning, studies have also shown that removal of lead stores through chelation therapy has produced significant improvements in behavior.(Ruff). Agents frequently used for heavy metal chelation include ethylene diaminetetraacetic acid (EDTA), dimercaptosuccinic acid (DMSA), d-penicillamine, and dimercaptoproponol. These are often given in oral doses, alone or in combination, and in disrupted schedules days, such as 3 days per week.

Controversy exists with respect to whether moderately elevated lead levels are toxic in certain children with various central nervous system dysfunctions. One way of addressing this controversy is to remove the lead; if the condition is ameliorated a presumption of toxicity becomes reasonable. Such a strategy is reported herein.

Children with an operationally defined central nervous system dysfunction (hyperactivity) and moderately elevated lead levels were treated with a lead chelating agent in a random allocation double blind treatment regimen. Statistically significant and obvious behavioral improvement was reported by three separate evaluators (i.e., parent, teacher, and treating physician) of the child, suggesting a toxic relationship between moderately elevated lead levels and hyperactivity.

Historically, chelation treatment for lead has been limited to acute or severe poisoning of lead. Others have recommended strategies use chelation therapy for even low levels of lead. One clinical impact and cost-effectiveness study made an estimate that treatment strategies for 1.4% of United States preschoolers whose blood lead levels are 2.21 mumol/L (25 mcgs/dL) or higher could prevent more than $900 million per year in overall costs when the costs of remedial education are considered. (Glotzer)

Evidence also suggests that, even in cases of acute poisoning, the therapy and long-term management of lead toxicity may not have been aedquate. In one study of lead-poisoned children who had been medically chelated, their routine school-administered developmental test scores after treatment (average 4.5 months post treatment) had declined significantly, compared to test scores before the poisoning occurred, indicating significant residual effects. (Kirkconnell) Treatment for lead poisoning in these children may require ongoing treatment with chelating agents and periodic re-evaluation for levels of lead. This concept may also apply to those effected children with lower levels of exposure. Efforts to identify and remove potential sources of lead and other toxic metals may require ongoing diligence to reduce environmental exposure, as well as periodic use of oral chelating agents in those who maintain toxic levels.

Use of chelating agents generally requires a prescription and physician supervision. Some supplement companies have begun to offer products in their physician line designed for this purpose, containing such chelators as EDTA and DMSA in small to moderate doses.

Some natural, nutritional products may also have mild chelating properties. Among the over-the counter products with potential for their ability to assist in chelation of heavy metals are:

Fucus ( Pro-Algin), a sea vegetable,

Chlorella, a blue-green algae

Alpha lipoic acid (100200 mg 3x/day) also helps maintain optimal levels of reduced-glutathione for improved biological conjugation and clearing of these and other toxic substances.

A Report from the Clean Water Fund and Physicians for Social Responsibility: In Harm's Way

A report issued by the Clean Water Fund and Physicians for Social Responsibility released a report during May which found that the blood levels of lead in at least one million U.S. children now have reached a level that could affect behavior and cognition.

The report also states that over 80 percent of adults and 90 percent of US children have pesticide residue in their bodies. The report entitled "In Harm's Way" evaluates the effects of metals including mercury, lead, cadmium, and manganese. It also examines pesticides, dioxins and PCBs, solvents used in gasoline, paints, glues and cleaning solutions, as well as nicotine and alcohol.

The intestines are home to a vast ecology of microorganisms. These living organisms produce and eliminate various waste products in their metabolism. Some of these biomarkers of intestinal flora are known to have neurotoxic effects. Over-growth of pathogenic organisms and imbalanced intestinal ecology are known to produce significant amounts of these endotoxins, which can be measured, quantified, and identified as yeast or bacterial in origin. Certain of these compounds have been identified in urine of children with ADD, ADHD, autism, and other psychiatric disorders (Shaw). Refer also to information on urinary organic acids testing at Great Plains Laboratory

Problems with gastrointestinal flora, or gut ecology, can be addressed through a pro-biotic program, consisting of biological therapies, such as:

A good physical exam is one important part of the physicians evaluation for nutritional aspects of illness. Signs of nutritional deficiency may be evident to the nutrition-oriented physician. (Refer to the textbook, Nutrition from Marz, by Russel Marz, ND, for detailed information on the nutrition physical.)